1. Field of the Invention
The present invention relates to phenalenone derivatives which are formed by the microorganism Penicillium herquei Bainer & Sartory, DSM 14142 during fermentation, processes for their preparation, their use as pharmaceutical compositions, and their use for the treatment or prophylaxis of bacterial infections, mycoses, oncoses and rheumatic diseases.
2. Description of the Art
Cancer is a disease of humans and animals which usually takes a fatal course and which is caused by the uncontrolled growth of endogenous cells. Cancer is the term for the formation of malignant growths (malignomas), of neoplasms (tumors and carcinomas) or for the malignant degeneration and maturation disorder of white blood cells (leukemia, blood cancer). Cancer or tumor cells are formed by conversion of endogenous cells. The malignancy of the cancer cell is expressed in the autonomy of growth, that is, its ability to grow is uninhibited in an infiltrating manner and without classification in the constructional plan of the organs and with tissue destruction. A certain sign of malignancy is the formation of tumor-remote deposits (metastases) after hematogenic or lymphogenic spread of tumor cells. Cancer is among the most frequent causes of death of man and therefore there is a great need for methods and means for the cure or treatment of malignant degenerations.
Possible therapy for malignant tumors includes, in addition to radical surgical removal of the tumor where possible, radiological therapy using X-rays, α-, β-, γ-rays, immunotherapy and chemotherapy. Immunotherapy can at present only be used to a restricted extent. The chemotherapy of tumors is understood as meaning the administration of cell toxins (cytostatics) for the treatment of tumors and of remaining tumor cells after local surgical treatment or irradiation. These substances specifically intervene in certain processes of cell division, so that tissue having a high proportion of dividing cells, such as the rapidly growing tumor tissue, react more sensitively. Alkylating compounds, such as, for example, cyclophosphamide, (The Merck Index, 12th ed. page 463), antimetabolites, such as methotrexate (The Merck Index, 12th ed. page 1025), alkaloids, such as vincristine (The Merck Index, 12th ed. page 1704) and antibiotics, such as daunomycin (The Merck Index, 12th ed. page 479) and adriamycin (The Merck Index, 12th ed. pages 581-582) are used. However, all of these agents feature certain disadvantages on account of severe side effects, so that the death of the afflicted person is only delayed, but not averted. Moreover, in degenerated (cancer) cells, when resistance to the agents used occurs, the present medicaments then no longer act cytostatically, but exhibit toxic side effects. Moreover, it has been shown that a combined or sequential administration of cytostatics augments the activity of an individual cytostatic (monotherapy) and it is thereby possible that significant side effects are not additive in polychemotherapy. For all these reasons, novel chemotherapeutics are urgently needed and therefore sought worldwide.
Natural substances having a phenalenone parent structure have already been described. Phenalene is a fused, partially aromatic ring system, which decomposes in air. Phenalenone is its oxidation product having a carbonyl group in the 1-position.
The patent application WO 99/60992 generically describes phenalenones, which in all positions apart from C1 can be substituted by hydrogen or C1-C4-alkyl, preferably methyl, or C1-C4-alkoxy, preferably methoxy, for use as hair colorants.
Japanese patent application JP 60199849 describes the phenalenone derivative 2,7,8,9-tetrahydroxy-4-methoxy-5-methylphenalen-1-one, which is active as a phosphodiesterase (PDE) inhibitor and can be used for the treatment of arteriosclerosis, bronchial asthma, diabetes and cancers.
D. A. Frost & G. A. Morrison; (J. Chem. Soc., Perkin Trans. 1, 20, 2388-2396, 1973) describe the isolation of norxanthoherquein (2,3,4,7,8,9-hexahydroxy-5-methyl-phenalen-1-one) from Penicillium herquei Bainer & Sartory.
D. H. R. Barton et al. (Tetrahedron, 6, 48, 1959) describe the isolation of atrovenetin from Penicillium atrovenetum and from Penicillium herquei Bainer & Sartory. Atroventin is described as an antioxidant by Y. Ishikawa et al. (J. Am. Oil Chem. Soc. 68, 666-668, 1991), and as a cytostatic having antineoplastic activity in WO 00/45165.
N. Narasimhachari and L. C. Vining (J. Antibiotics, 25, 155, 1972) and J. Simpson (Chem. Soc. Perkin Trans. 1, 1979, 1233-1238) describe tautomeric forms of the compound desoxyherqueinone (2-O-methylatrovenetin), which are isolable from Penicillium herquei and exhibit antibiotic activity against gram-positive organisms.
The object of the present invention is to provide alternative phenalenone derivatives which can be used in tumor therapy.